title: Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections.
abstract: Viruses such as influenza suppress host immune function by a variety of methods. This may result in significant morbidity through several pathways, including facilitation of secondary bacterial pneumonia from pathogens such as Streptococcus pneumoniae. PKH26-phagocytic cell labeling dye was administered intranasally to label resident alveolar macrophages (AMs) in a well-established murine model before influenza infection to determine turnover kinetics during the course of infection. More than 90% of resident AMs were lost in the first week after influenza, whereas the remaining cells had a necrotic phenotype. To establish the impact of this innate immune defect, influenza-infected mice were challenged with S. pneumoniae. Early AM-mediated bacterial clearance was significantly impaired in influenza-infected mice: ~50% of the initial bacterial inoculum could be harvested from the alveolar airspace 3 h later. In mock-infected mice, by contrast, >95% of inocula up to 50-fold higher was efficiently cleared. Coinfection during the AM depletion phase caused significant body weight loss and mortality. Two weeks after influenza, the AM population was fully replenished with successful re-establishment of early innate host protection. Local GM-CSF treatment partially restored the impaired early bacterial clearance with efficient protection against secondary pneumococcal pneumonia. We conclude that resident AM depletion occurs during influenza infection. Among other potential effects, this establishes a niche for secondary pneumococcal infection by altering early cellular innate immunity in the lungs, resulting in pneumococcal outgrowth and lethal pneumonia. This novel mechanism will inform development of novel therapeutic approaches to restore lung innate immunity against bacterial superinfections.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Hazem E
authors.initials: HE
authors.lastname: Ghoneim
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: McCullers
mesh_terms: D000818:Animals; D060085:Coinfection; D005260:Female; D008168:Lung / Q000382:microbiology / Q000821:virology; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009930:Organic Chemicals; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000276:immunology*; D011008:Pneumococcal Infections / Q000150:complications / Q000276:immunology* / Q000517:prevention & control; D013296:Streptococcus pneumoniae / Q000276:immunology; D015163:Superinfection / Q000150:complications / Q000382:microbiology*
chemical_list: D009930:Organic Chemicals; C070080:PKH 26